PROJECT SUMMARY SNX27 is a member of a large family of PX-domain proteins which mediate protein trafficking and sorting from the endosome. Highly enriched in human brain, SNX27 facilitates endosome to cell surface trafficking of numerous transmembrane signaling components; our work shows that SNX27 mediated surface distribution of the ionotropic AMPA receptor subunit GluR1 is impaired in Down?s syndrome (DS) through triplication of the miR-155 locus on human Chromosome 21 which attenuates SNX27 expression through a C/EBP?-dependent mechanism. Our work also indicates that SNX27 function is fundamental to proper ciliated ependymal layer formation within lateral brain ventricles, where deletion of SNX27 results in early-stage hydrocephalus. Interestingly, our preliminary data demonstrates that SNX27 signaling is critical in Alzheimer?s disease (AD) through the regulation of amyloidogenic processing of the Amyloid Precursor Protein (APP): SNX27 limits A? generation through impairment of the ?-secretase complex, and through enhancing endosome to cell surface trafficking of a SORLA/APP complex. Together, these results demonstrate that SNX27 is a critical signaling junction which can affect developmental and pathological outcome in various neurological disorders. As SNX27 function is impaired in these disorders, enhancing SNX27 function may be an effective means to restore brain dysfunction in DS, hydrocephalus and AD. The focus of this study is to characterize and exploit SNX27-dependent pathways to restore and repair dysfunctional SNX27 signaling/trafficking nodes in DS and AD. Similar to SNX27 deletion strains, DS mouse models also feature hydrocephalus (DS-hydrocephalus) and ventriculomegaly phenotypes. We will use DS- hydrocephalus as a model system to characterize SNX27-dependent hydrocephalus pathways, and determine whether SNX27 modulation can affect DS-hydrocephalus phenotypes. As we have previously shown that SNX27 haploinsufficiency induces A? accumulation in AD cell and animal models, we will determine whether SNX27 overexpression can have restorative effects in reducing amyloidogenic A? generation, restore synaptic/cognitive deficits in an AD background and DS background, and determine whether these effects are dependent on SORLA trafficking. As our preliminary results indicate that impairment of SNX27 function drives certain aspects of DS and AD pathogenesis, enhancing SNX27/target interactions will likely restore SNX27-associated impairment in DS and AD. We will therefore explore molecular mechanisms of SNX27 interactions with downstream pathological targets such as GluR1 and SORLA, and screen for small molecules that may enhance SNX27 interaction and trafficking of its targets. As SNX27-associated impairment may span a variety of neurological disorders (DS, hydrocephalus and AD), enhancers of SNX27 function may have restorative effects in a variety of neurodegenerative contexts. Results from this study may yield mechanistic insight into how SNX27 defects may influence DS and AD, and define strategies to restore SNX27 function in these disorders.